European Annals of Otorhinolaryngology, Head and Neck diseases 135 (2018) S23–S28

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International consensus

International consensus (ICON) on treatment of sudden sensorineural

hearing loss
M. Marx a,b,∗ , E. Younes a,b , S.S. Chandrasekhar c , J. Ito d , S. Plontke e , S. O’Leary f ,
O. Sterkers g,h
a
Department of otology and neurotology, Purpan hospital, CHU de Toulouse, 1, place du Dr-Baylac, 31059 Toulouse, France
b
Paul-Sabatier Toulouse 3 University, 31062 Toulouse, France
c
New York otology, New York, NY, USA
d
Department of otolaryngology, head & neck surgery, graduate school of medicine, Kyoto university, Kyoto, Japan
e
Department of otorhinolaryngology, head and neck surgery, university hospital Halle (Saale), Martin Luther university Halle-Wittenberg, Halle (Saale),
Germany
f
Department of otolaryngology, university of Melbourne, Royal Victorian eye and ear hospital, East Melbourne, Australia
g
Unité otologie, implants auditifs et chirurgie de la base du crâne, groupe hospitalier Pitié-Salpêtrière, 75651 Paris cedex 13, France
h
UMR-S 1159 Inserm, université Paris 6 Pierre-et-Marie-Curie, 78890 Paris cedex 18, France

a r t i c l e i n f o a b s t r a c t

Keywords: Sudden sensorineural hearing loss (SSNHL) is a common and alarming symptom that often prompts an
Sudden hearing loss urgent visit to an ENT specialist. Treatment of SSNHL remains one of the most problematic issues for con-
Randomized controlled trial temporary otorhinolaryngology: although many meta-analyses and national guidelines have been issued,
Trans-tympanic steroids
management is not standardized in terms of medical treatment, and duration and route of administra-
tion. We present several methodological suggestions for the study of treatments for SSNHL. These were
developed from the existing level of evidence of the main treatments used in SSNHL by experts who
convened at the IFOS 2017 ENT World Congress in Paris, France. All panelists agreed that one of the main
limitations present in studies on SSNHL is related to the wide heterogeneity, which characterizes both the
initial hearing deficit and the amount of hearing recovery. Although evidence of the efficacy of systemic
steroids cannot be considered as strong enough to recommend their use, it is still the most widespread
primary therapy and can be considered as the current standard of care. Therefore, systemic steroids stand
as an adequate control for any innovative treatment. To reduce the number of subjects we suggest that
the inclusion criteria should be restricted to moderate to profound levels of hearing loss. The efficacy of
trans-tympanic steroids as a salvage therapy was suggested in several reports on small populations and
needs to be confirmed with larger randomized controlled trials.
© 2018 Elsevier Masson SAS. All rights reserved.

1. Introduction hypotheses have been proposed. The most common theories

Although sudden sensorineural hearing loss (SSNHL) has a rel-
atively low incidence of 5 and 30 cases per 100,000 per year [1], it
is considered one of the most common emergencies in ENT prac-
tice. SSNHL is usually defined as a unilateral hearing loss of at least
30 dB HL in three consecutive frequencies in the standard pure-
tone audiogram [1,2] and can present at varying levels of severity
from mild to total. SSNHL is considered idiopathic in the absence
of established etiology, although several pathophysiological
∗ Corresponding author.
E-mail address: marx.m@chu-toulouse.fr (M. Marx).
include viral infection [3,4], rupture of the cochlear membrane
[5,6] and vascular accident [7–9]. The evolution of the condition
is marked by a high rate of spontaneous recovery; estimated at 32%
to 65% in case histories and placebo-controlled studies [10–12]. The
audiogram characteristics have been shown to influence the evo-
lution [11–14] with low and mid-frequency hearing losses given
a better prognosis that flat and severe losses. There is general
agreement that the management of SSNHL should start with diag-
nostic MRI scanning of the cerebello-pontine angle to discard a
vestibular schwannoma [1,2,15,16] and search for a demyelinat-
ing process or a labyrinthine haemorrhage [17]. The treatment of
SSNHL appears more controversial and the necessity of medication
has even been questioned by several authors [18,19]. Different ther-
apeutic approaches are based on the supposed pathophysiological

https://doi.org/10.1016/j.anorl.2017.12.011
1879-7296/© 2018 Elsevier Masson SAS. All rights reserved.
S24 M. Marx et al. / European Annals of Otorhinolaryngology, Head and Neck diseases 135 (2018) S23–S28
mechanisms responsible for inner ear dysfunction: For example
steroids to reduce the supposed inflammatory response to hyper-
baric oxygenation to reverse the lack of oxygen in the inner ear. The
heterogeneity of hearing deficits and their evolution, the diversity
of possible causes and corresponding treatments are all factors that
challenge evidence-based practice.
Several systematic reviews of the literature have been con-
ducted on the effectiveness of steroids as a treatment for SSNHL
in randomized controlled trials (RCT). By far most of these under-
lined the heterogeneity of inclusion criteria or outcome measures.
Indeed, the inclusion of subjects with highly variable levels of hear-
ing loss, accompanying symptoms (vertigo and tinnitus) or delays
after onset of hearing loss can lead to a significant risk of selec-
tion bias and unmatched groups. Likewise, the wide variety of
criteria used to describe the evolution of hearing function, from
different definitions of pure-tone average threshold to multiple
categorical classifications, reduces the relevance of comparisons
made between studies. As a result, steroids are one of the most used
options among the therapeutic armamentarium without any strong
recommendation to refer to. Oral steroids are usually proposed as
a first-line treatment based on an evaluation of the ratio risk ver-
sus benefit. The potential consequences of unilateral SSNHL may be
severe in terms of quality of life, because of the impact on speech
recognition in noise, on sound localization and because of the inca-
pacitating tinnitus sometimes associated [19–21]. In contrast, the
side effects expected from an acute therapy with oral steroids are
mild [22,23]. Trans-tympanic steroids can also be proposed as a sin-
gle primary therapy [22], but have more frequently been assessed
in combination with systemic steroids [24] or as a salvage therapy
[25].
This present consensus conference was held in Paris during
the International Federation of Oto-rhino-laryngological Societies
(IFOS) 2017 congress, with two purposes: The first objective was
to provide an updated and documented overview of the level
of evidence supporting the treatment of SSNHL with systemic
and trans-tympanic steroids. The second goal of this international
consensus conference was to identify methodological guidelines,
which should be considered when designing studies on treatments
for SSNHL.
Members of the discussion panel were S. Chandrasekhar (USA),
J. Ito (Japan), S. Plontke (Germany) and S. O’Leary (Australia), each
one being an international leading expert in the field on SSNHL.
The discussion was moderated by M. Marx (France) and O. Sterkers
(France).
1.1. Level of evidence for the use of steroids
1.1.1. Systemic steroids
Systemic steroids as a treatment for SSNHL have been exten-
sively studied since the hallmark work by Wilson et al. in 1980
[26]. This paper is often cited (> 900 citations) to support the effec-
tiveness of systemic steroids and warrants some further discussion:
based on a significant difference between the proportion of patients
who improved in the group who received steroids (20/33 subjects
i.e. 61%) and the proportion in the placebo-controlled group (11/34,
i.e. 32%), the authors concluded that steroids improved hearing
better than placebo, and more specifically in a “steroid-effective”
zone corresponding to moderate hearing loss. In fact, patients were
included in two different centers with different steroid treatments
(dexamethasone and methylprednisolone) at varying doses. The
distribution of age; prevalence of accompanying symptoms such
as vertigo; and audiogram profiles differed between treatment
group and control group so that the randomization procedure was
inadequate if at all present. Furthermore, there was a significant
difference in the rate of recovery between the two centers both for
oral steroids (73% versus 36%) and for placebo (50% versus 31%) so
that the data should not have been pooled.
However, this article was selected for review in the Cochrane
work on this topic, first published in 2006 and most recently
updated in 2013 [27]. In this review, only 3 publications were
included despite more than 200 studies being described as RCTs.
In the same way, two [28,29] to four papers [26,28–30] were
eventually selected over hundreds of studies in several reviews or
meta-analyses [31–33] because of the global rarity of genuine RCTs.
As for the Cochrane review and the clinical guidelines of the Ameri-
can Academy of Otolaryngology – Head & Neck Surgery (AAO-HNS)
these papers [31–33] concluded that systemic steroids were not
proven as either effective or ineffective. No recommendation can
therefore be made for or against their usage, but because of the
potentially severe consequences of SSNHL, the AAO-HNS guideline
suggested using them as an option. The most common dose used for
the prescription of oral prednisolone is 60 mg per day (i.e. approx-
imately 1 mg/kg) but higher doses are for instance recommended
in Germany (at least 250 mg per day for the first three days [34]).
A recent RCT comparing high-doses (500 mg per day for three days
followed by 60 mg per days for 11 days) to the common regimen
(60 mg per day for 14 days) showed no significant benefit of using
higher doses [35]. Nevertheless, it should be noted that the number
of subjects needed to treat was not reached (67 subjects included
versus 106 calculated).
1.1.2. Trans-tympanic steroids
The main theoretical advantage of trans-tympanic steroids
relies on the bypass of the blood-labyrinthine barrier to reach
higher concentrations in the inner ear [36,37]. Further, this mode of
administration avoids the undesirable effects of systemic steroids.
The global effectiveness of trans-tympanic steroids in the treat-
ment of SSNHL is hard to determine because they may be used as
a primary therapy alone [22,38–41] or in combination with sys-
temic steroids [24,42,43], or as a salvage therapy after failure of
systemic steroids [25,44–46]. Several recent meta-analyses [47,48]
showed no significant difference in terms of pure-tone average
(PTA) improvement and recovery rate between systemic and trans-
tympanic steroids, when used as a primary therapy. However, the
meta-analysis by Qiang et al. [49] found a better recovery rate in a
total of 225 pooled subjects who received a first-line treatment by
trans-tympanic steroids compared to 226 pooled control subjects
(systemic steroids), especially in subjects with mild to moderate
hearing loss. An ongoing Cochrane review led and presented by
S. Plontke emphasizes that the majority of such RCTs include small
samples and offer limited possibilities to assess the risk of bias.
Most studies on the use of trans-tympanic steroids as a sal-
vage therapy showed at least a tendency to obtain better results
than control for PTA improvement and/or the rate of recovery
[25,44–46]. As a result, a recent meta-analysis performed on five
studies [25,44–46,50] found a mean PTA improvement of 11.54 dB
for trans-tympanic steroids versus 2.68 dB for placebo or no treat-
ment controls [51]. The limited sample size of generally < 30 should
also be taken into account for the interpretation of such results.
The main RCTs using systemic and/or trans-tympanic steroids as a
primary therapy are summarized in Table 1.
1.2. Methodological implications
RCTs are unanimously acknowledged as the gold standard in
evaluating the effectiveness of a treatment, but not all RCTs are
equal in value, which is particularly true in the field of SSNHL. Sig-
nificant limitations, from the conception of the study design up to
the reporting of the methods and outcomes, were cause for rejec-
tion of these studies in the recently updated Cochrane review [27].
The general low quality of trials on SSNHL is regularly underlined in
 M. Marx et al. / European Annals of Otorhinolaryngology, Head and Neck diseases 135 (2018) S23–S28
Table 1
Study characteristics of systemic steroids and/or trans-tympanic steroids (TTS) as a primary therapy for SSNHL.
Authors
Systemic steroids
Wilson et al., 1980
Nosrati and Hultcrantz, 2012
Cinamon et al., 2001
Eftekharian et al., 2015
Trans-tympanic steroids
Lim et al., 2012
Rauch et al., 2011
Swachia et al., 2016
Gundogan et al., 2013
Filippo et al., 2013
Hong et al., 2009
Dispenza et al., 2011
Number of Comparison
subjects (n)
n = 67 Steroids (n = 33, two different
steroid treatments) vs. placebo
(n = 34)
One “control” group of 52 (or
53?) subjects added; without
any treatment
n = 93 Prednisone (n = 47) vs. placebo
(n = 46)
n = 41 Carbogen inhalation (n = 11),
room air (n = 9), prednisone
(n = 10), placebo (n = 11)
n = 67 Pulse steroid therapy (n = 29)
with 500 mg/day for 3 days
then 60 mg/day vs. standard
steroid treatment (n = 31) with
60 mg/day
n = 60 Oral steroids (20), TTS (20),
oral and TTS combined (20)
n = 250 Oral steroids (n = 129) vs. TTS
(n = 129)
n = 42 Oral steroids (n = 21) vs. TTS
(n = 21)
n = 73 Oral steroids (n = 36) vs. oral
and TTS combined (n = 37)
n = 50 TTS (n = 25) vs. placebo (n = 25).
If no improvement at day 7,
supplementary oral
prednisolone given for 8 days
n = 63 Oral steroids (n = 31) vs. TTS
(n = 32)
n = 46 Oral steroids (n = 21) vs. TTS
(n = 25)
Outcome
measures
Hearing recovery: complete:
within 10 dB of initial PTA/SRT;
partial: > 50% of initial PTA/SRT; no
recovery: < 50% of initial PTA/SRT
PTA and rate of PTA improvement
(> 10 dB)
Rate of complete recovery (within
10 dB of initial PTA)
Rate of PTA improvement (> 15 dB)
Pure-tone improvement per
frequency (0.5, 1, 2, 3, 4 kHz)
Word recognition score
improvement
Complete, partial or absence of
recovery, as defined by the
AAO-HNSa
PTA and SRT improvements
Complete, partial or absence of
recovery, as defined by the
AAO-HNSa
PTA and rate of PTA improvement
(> 10 dB)
Rate of complete recovery
(PTA < 30 dB)
Word recognition score
PTA improvement
Furuhashi criteriab
PTA improvement
Word recognition score
Siegel’s criteriac
PTA improvement
Furuashi criteriab
PTA and pure-tone thresholds
improvement
Siegel’s criteriac
PTA and rate of PTA improvement
(> 10 dB)
S25
Outcomes
If hearing loss > 90 dB, no effect of
steroids
Definition of a “steroid-effective
zone”, with hearing better than
90 dB
Rate of recovery in the
placebo-controlled study for
hearing losses < 90 dB: 91% with
steroids vs. 40% with placebo in
one center, 57% vs. 36% in the other
No significant difference between
prednisone and placebo at day 90:
mean PTA improvement of 39 dB
(± 20.1) with prednisone, 35.1 dB
(± 38.3) with placebo; 18/47
complete recovery with
prednisone, 18/46 complete
recovery with placebo
Overall improvement = 73.1%
(30/41)
No difference between 4 groups
No difference between groups for
pure-tone, word recognition
scores, or rate of recovery
Group pulse: 7/29 complete, 10/29
partial, 12/29 no recovery
Group standard: 6/31 complete,
11/31 partial, 14/31 no recovery
No significant difference between
groups. Trend for better results
combined therapy (mean
improvement of 22 dB vs. 12.1 dB
and 12.8 dB for oral or TTS alone)
No inferiority of TTS compared to
oral steroids: 28.7 dB vs. 30.7 dB
PTA improvement; 24% vs. 20% of
complete recovery
No significant difference between
groups: improvement of
18.24 ± 8.72 dB with oral
prednisone and 14.68 ± 12.88 dB
with TTS
Significantly better results with
combined therapy on: PTA: 44
dB ± 21.5 vs. 25.7 dB ± 19.8
improvement; word recognition
score and rate of recovery
At day 7, significantly better results
with TTS over placebo on: PTA
improvement; rate of recovery
(19/25 complete recovery with TTS
vs. 5/25 with placebo); 1 month
after, no significant difference
between groups
Significant difference for pure-tone
improvement in high frequencies:
better with oral steroids
No significant difference for the
rate of recovery
No significant difference between
groups: 20/25 with TTS and 17/21
with oral steroids; numbers for
PTA improvements not reported
S26 M. Marx et al. / European Annals of Otorhinolaryngology, Head and Neck diseases 135 (2018) S23–S28

Table 1
(Continued)

Authors Number of Comparison Outcome Outcomes

subjects (n) measures

Battaglia et al., 2008
n = 51 TTS + oral placebo taper (n = 17)
vs. high-dose prednisone taper
(HDPT) and trans-tympanic
placebo injections (n = 18) vs.
combined TTS and HDPT
(n = 16)
PTA and rate of PTA improvement
(> 15 dB)
Word recognition score and rate of
improvement > 25% points
Greater improvement for PTA and
word recognition with combined
therapy
Better rate of complete recovery
for combined therapy compared to
treatment by HDPT

SSNHL: sudden sensorineural hearing loss; PTA: pure-tone average; SRT: speech recognition threshold.
a
AAO-HNS criteria. Complete recovery with return to within 10 dB HL of the unaffected ear and recovery to word recognition score to within 5% to 10% of the unaffected
ear. Partial recovery defined in 2 ways (clinically meaningful/not meaningful recovery based on whether or not the degree of initial hearing loss after SSNHL rendered the
ear nonserviceable). No recovery: anything less than 10 dB HL.
b
Furuashi criteria. Complete recovery: PTA ≤ 25 dB HL or identical to the contralateral non-affected ear. Marked recovery: PTA improvement > 30 dB HL. Slight recovery:
PTA improvement between 10 and 30 dB HL. No recovery: anything less than 10 dB HL.
c
Siegel’s criteria. Complete recovery: PTA ≤ 25 dB HL or identical to the unaffected ear. Partial improvement if improvement > 15 dB HL and final PTA between 25 and 45 dB
HL. Slight improvement if improvement > 15 dB HL and final PTA poorer 45 dB HL. No recovery if improvement ≤ 15 dB HL and final PTA poorer than 75 dB HL.

the conclusion of other literature reviews or meta-analyses [31,33].
It must be recognized that the relative rarity of SSNHL, combined
with the heterogeneous level of hearing deficits and the high rate of
spontaneous recovery, usually complicates the conception of stud-
ies and the analyses of the outcomes. But several suggestions were
made during the international consensus conference to improve
the global quality of RCTs in that field.
1.2.1. Inclusion criteria
Although it has an impact on the ease of recruitment, the restric-
tion of inclusion criteria is a good solution to reduce the initial
heterogeneity, and the level of hearing loss is probably the most
variable characteristic in subjects with SSNHL. Several valuable
studies thus selected only patients with moderate hearing loss [52]
or with at least moderate hearing loss [22,25,35] to study the effect
of steroids in a relatively homogeneous populations. It might be all
the more relevant to focus on these patients as the probability of
spontaneous recovery (and its influence on outcomes) is reduced
in case of severe to profound hearing loss [10,11,53].
1.2.2. Outcome measures
The question of the outcome measures, which should be cho-
sen is prominently controversial. This can be illustrated by the
multiplicity of categorical criteria existing in the literature. The
landmark study by Wilson et al. [26] defined recovery as complete
if the follow-up PTA (dB HL) or speech recognition threshold (SRT)
improved to within 10 dB of pre-sudden hearing loss hearing lev-
els. Complete recovery was differently defined using Furuashi or
Siegel’s criteria as a final PTA better than 25 dB HL [43,52,54,55], or
by the ministry of health, Labor and Welfare in Japan as final PTA
better than 20 dB HL [56]. If the definition of complete recovery is
so problematic, it is not hard to imagine the variety of definitions
for “marked” or “slight” recovery. Likewise, the restoration of useful
hearing is a notion, which may generate multiple interpretations.
In certain patients, it can refer to PTA allowing speech recognition
with a hearing aid. In others, the restoration of hearing thresholds
compatible with the perception of some environmental sounds.
It is obvious that “ideal” hearing measurements should include
pre- and post-treatment pure-tone thresholds and word recogni-
tion scores but the reporting of the evolution of these parameters
remains problematic. To compensate for the lack of standardization
for reporting combinations of hearing performance Gurgel et al.
[57] proposed a classification system basing on a scattergram; they
plotted pure-tone thresholds against recognition scores for words.
However, this is still mainly used only for the English language.
Furthermore, there is unfortunately no validated tool to assess
the equivalence of speech recognition tests across the different
languages and pure-tone audiogram remains the only true inter-
national common standard.
Therefore, the panelists suggested using the change in pure-tone
thresholds as the primary outcome measure for studies on treat-
ments for SSNHL. It was added that any PTA change exceeding 10 dB
HL could be considered as significant if the audiometry was per-
formed under adequately controlled conditions [58]. Besides the
absolute evolution of pure-tone thresholds a 10 dB change in PTA
could thus serve as a categorical criterion to determine the pres-
ence or absence of hearing improvement. Likewise, the use of final
pure-tone threshold allows the definition of complete recovery as
a secondary outcome measure. The evolution of speech recogni-
tion scores after treatment remains highly informative, as well as
the proportion of subjects improving in each treatment group for
PTA and word recognition. The duration between the onset of the
hearing loss and the final PTA measurement is also variable in the
literature, from 30 days [52] to 3 months [30], although longer
intervals allow including delayed recoveries.
1.2.3. Calculation of the sample size
The calculation of the sample size is an element regularly lack-
ing in studies on SSNHL although it should appear as stated in
the general guidelines for the reporting of randomized controlled
trial published by the Consolidated Standards of Reporting Trials
(CONSORT) group [59]. It is not uncommon to calculate numbers of
subjects needed to treat greater than 150–200 to show an advan-
tage of a treatment over natural evolution with the significant
rate of spontaneous recovery [60]. However, such sample sizes are
built upon the assumption that all patients can improve, while
the inter-individual variability for hearing recovery is an intrin-
sic characteristic of SSNHL. Actually, both spontaneous evolution
and uneven distribution of recovery should be taken into account
to model the sample size. During his presentation, S. O’Leary
demonstrated that this number could decrease significantly if only
subjects with moderate and more severe levels of hearing loss were
included. He also emphasized the need to apply non-parametric
statistics to the analyses of the outcomes because of the non-normal
distribution of hearing recovery.
1.2.4. The control group
The nature of the control group is also a matter of debate and
influences the choice of hypothesis. The question of effectiveness
of a new treatment for SSNHL theoretically requires a placebo con-
trol. Numerous RCTs were for instance excluded from the Cochrane
review because the true effect of steroids could not be determined
in the absence of such a group [22,37,38,41,61–67]. However, some
of these studies addressed a more relevant question from a clinical
point of view, which is the superiority of a new treatment over the
 M. Marx et al. / European Annals of Otorhinolaryngology, Head and Neck diseases 135 (2018) S23–S28
standard of care. Systemic steroids can be considered as the current
clinical practice and are for sure the most widely used treatment, as
demonstrated in several surveys [68,69] with rates of prescription
by otolaryngologists as high as 100% [69]. These clinical consid-
erations question the ethical value of placebo in the assessment
of treatments for SSNHL. All panelists agreed that a new treat-
ment should provide better hearing results than steroids to deserve
further attention from the medical community but also from the
regulatory authorities.
Insulin-like growth factor-1 (IGF1) in topical application to treat
SSNHL is a good example of an innovative therapy: IGF-1 plays
a role in the protection of cochlear hair cells [69,70] which may
be damaged to various degrees in cases of SSNHL. Initial animal
experiments showed the safety of IGF-1 and suggested its effi-
cacy by protecting hair cells from noise exposure, ischemic injury
[69,71,72] and ototoxic drugs [70]. Pilot clinical trials in a limited
number of subjects with refractory SSNHL followed these results
to demonstrate safety and efficacy of trans-tympanic topical IGF-1
delivered using gelatin hydrogels [73,74]. A larger multicenter RCT
was finally performed to compare topical IGF-1 to the standard
trans- tympanic dexamethasone treatment as a salvage therapy
[75]. In this RCT the primary outcome measure was the rate of
improvement (change in PTA > 10 dB). The sample size (n = 120) was
calculated basing on the expected proportions of subjects improv-
ing after each treatment determined by the previous clinical trials
for IGF-1 and the main recent findings in the literature for dex-
amethasone. Randomization was stratified by the mean hearing
thresholds to distribute equally the number of profound hearing
losses. The primary objective of the trial was not achieved because
the proportion of subjects improved did not differ significantly
between the two groups with a rate of 66.7% in IGF-1 group and
53.6% in dexamethasone group, but the change in PTA was more
favorable in IGF-1.
2. Conclusion
SSNHL is a difficult condition to study because of the wide het-
erogeneity, which characterizes both the initial hearing deficits and
the amount of hearing recovery. Although the evidence support-
ing their efficacy is still debated, systemic steroids are the most
widespread primary therapy and stand as an adequate control for
any innovative treatment for SSNHL. Likewise, the true effect of
trans-tympanic steroids used as a salvage therapy is debatable but
several RCTs showed significant hearing improvements in compar-
ison to control groups.
The statistical power of studies may be increased by restrict-
ing inclusion to moderate and more severe levels of hearing loss
and/or by the use of a stratified randomization. When modelled,
this restriction has also an influence on the calculation of the sam-
ple size, requiring a lower number of study subjects. Changes in
pure-tone thresholds are currently the only common, international
outcome measure and should therefore be employed in primary
end-points.
Disclosure of interest
The authors declare that they have no competing interest.
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